Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia

Area of Science:

• Oncology
• Immunology
• Neuroscience

Background:

• Cancer-induced cachexia and anorexia are severe complications with limited treatment options.
• The underlying mechanisms driving these syndromes are poorly understood.

Purpose of the Study:

• To identify the molecular and cellular mechanisms driving cancer cachexia and anorexia.
• To explore the tumor-immune-neural circuit involving growth and differentiation factor 15 (GDF15).

Main Methods:

• Utilized genetically engineered mouse models of pancreatic, lung, and skin cancers.
• Performed single-cell RNA sequencing to identify GDF15-producing cells.
• Investigated therapeutic interventions including GDF15-neutralizing antibodies, anti-CSF1R antibodies, and RET inhibitors.

Main Results:

• Loss of GDF15 protected against appetite, muscle, and fat loss in mouse cancer models.
• Macrophages were identified as a major source of GDF15, induced by tumor-derived CSF1.
• Disrupting the GDF15 feedforward loop significantly reduced cachexia and anorexia.

Conclusions:

• Identified a novel tumor-immune-neural circuit centered on GDF15 that drives cancer cachexia and anorexia.
• Demonstrated that GDF15 acts via the central nervous system to amplify cachexia.
• Highlighted the tumor-immune-neural triad as a potential therapeutic target for cancer-induced wasting syndromes.